PROJECT SUMMARY Hexavalent chromium [Cr(VI)] is a well-known environmental carcinogen. The exposure of Cr(VI), through contaminated soil, air particles and drinking water, is a major concern for the public health in the US and worldwide. While various means to protect the environment have dramatically reduced the onset of human diseases (including lung cancer) caused by the exposures of Cr(VI), there are still no effective strategies to prevent the pollution and to block the process of tumor promotion. This is because of the lack of the knowledge about the molecular targets involved in Cr(VI)-mediated carcinogenesis. Thus, there is an ugent need for elucidating the underlying mechanisms of Cr(VI)-mediated carcinogenic activities in cells. Studies have demonstrated that Cr(VI) exposure perturbs the state of redox, which then promotes uncontrollable cell growth and further tumorigenesis. However, the link between Cr(VI) exposure and tumorigenic tendency is not fully understood. Our preliminary data provided a novel observation that upon Cr(VI) treatment, the intracellular receptor src was activated in lung epithelial cells, which further triggered Ras signaling for the promotion of cell growth and transformation. We also demonstrated that the expression level of anti-apoptotic factor Bcl-2 was increased, which appeared through increasing its protein stability. Furthermore, the increase of Bcl-2 expression and activity was dependent upon Ras activation in Cr(VI)-mediated lung carcinogenesis. Based on the information, the long-term goal of our research is to elucidate the underlying mechanism of Cr(VI)-mediated tumorigenesis. We will use the obtained knowledge to design new means or inhibitors to target potential signaling molecules (perhaps src, Ras or Bcl-2), and to further validate their suppressive effects on Cr(VI)-induced transformation or carcinogenesis. Our immediate hypothesis of the proposal is that Cr(VI) exposure activates src/Ras signaling and further upregulates Bcl-2 for promoting lung cancer genesis and development. In order to test the hypothesis, two specific aims are formed: 1) to investigate the mechanisms by which Ras functions in Cr(VI)-induced transformation; and 2) to study how Bcl-2 stability is affected by Cr(VI) treatment for the promotion of tumorigenesis. The outcomes of these studies will provide valuable information to guide the development of new chemo-prevention methods and strategies of environmental protection from Cr(VI) pollution.